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MEDICINAL CHEMISTRY

COMBITORIAL CHEMISTRY

QSAR

ASSISTANT PROFESSORSARASWATI INSTITUTE OF PHARMACEUTICAL

SCIENCES

MR. SANDIP N. BADELIYA

What is medicinal chemistry ?

In medicinal chemistry, the chemist attempts to design and synthesize

a medicine or a pharmaceutical agent which will benefit humanity.

Such a compound could also be called a 'drug‘. Latin ars medicina,

meaning the art of healing

It involves:

• Synthesis

• Structure-Activity Relationships (SAR)

• Receptor interactions • Absorption, distribution, metabolism, and

excretion (ADME)

According to IUPAC:

Medicinal chemistry it concerns the discovery, the development, identification and

interpretation of mode of action of biological active compounds at the molecular level.

Medicinal chemistry covers the three stages

Discovery step: Involving choice of therapeutic target (receptor, enzyme &

target group, cellularorinvivomodel) & identification or discovery and

production of new active substances interactingwithselectedtargets. Such

compounds called LEADCOMPOUND.

An optimization step: Which deals with improvement of lead compound.

•The optimization process takes primarily into account the increase in

potency, selectivity and toxicity

Development stage: Whose purpose is continuation of improvement of

pharmacokinetic properties.

History of Medicinal chemistry

2000 BC Materia Medica 250 vegetables drug And 120 mineral drugs

1500 BC Egyptian papyrus ebers 700 drugs originated from

animal/plants/minerals

Emperor Frederick II issued the Magna Carta of pharmacy in 1240

Synthesis of Urea 1828 started Organic medicinal Chemistry

Ehrlich’s “Side chain theory” and chemotherapy and Fischer’s lock-and

key theory Birth of Modern Med Chem 1800

Medicinal chemistry received formal recognition in academic

pharmacy in 1932

Objective of medicinal chemistry !

Generally, we can identify the following stages in drug discovery, design and

development.

Drug discovery-finding a lead

• Choose a disease.

• Choose a drug target.

• Identify a bioassay.

• Find a lead compound.

• Isolate and purify the lead compound if necessary.

• Determine the structure of the lead compound if necessary.

Drug design

• Identify structure-activity relationships (SARs)

• Identify the pharmacophore.

• Improve target interactions (pharmacodynamics).

• Improve pharmacokinetic properties,

Drug development

• Patent the drug.

• Carry out preclinical trials (drug metabolism, toxicology, formulation and stability

test, pharmacology studies, etc).

• Design a manufacturing process (chemical and process development).

• Carry out clinical trials.

• Register and market the drug.

• Make money.

Finally Medicinal chemistry includes synthetic & computational aspects of the study

of existing drugs and agents in development in relation to their bioactivities i.e.,

understandings a SARs (Structure Activity Relationships). OR • Itisatailoring ofdrug

What is combitorial chemistry?

Combinatorial chemistry is a technique by which large numbers of

different but structurally similar molecules are produced rapidly and

submitted for pharmacological assay.

This technique uses the same reaction conditions with the same

reaction vessels to produce a large range of analogues.

Technique invented in the late 1980s and early 1990s to enable tasks to

be applied to many molecules simultaneously

Combitorial library

Def: collection of finally synthesized compounds

Size: depends on the number of building blocks used per reaction and the number of

reaction steps, in which a new building block is introduced

Typical: 102 up to 105 compounds

Random libraries Focused or targeted libraries

Multiple libraries Template –scaffold library

Multiple targets One target

Highly diverse Highly structural similarity

Mixtures Single compounds

˃ 5000 compounds ˂ ˂ 5000 compounds

Solid phase synthesis Synthesis in solution, solid phase

Non purified compounds Pure compounds

On bead screening, if possible Screening in solution

Applications

Applications of combinatorial chemistry are very wide Scientists use combinatorial

chemistry to create large populations of molecules that can be screened efficiently.

By producing larger, more diverse compound libraries, companies increase the

probability that they will find novel compounds of significant therapeutic and

commercial value.

Provides a stimulus for robot-controlled and immobilization strategies that allow

high-thrughput and multiple parallel approaches to drug discovery.

Techniques in combitorial chemistry

Solid support synthesis: (on solid phase such as resin bead, pins, or chips)

Split and mix method

Parallel synthesis

Solution phase synthesis (in solvent in the reaction flask

Solid phase synthesis

Reactants are bound to a polymeric surface and modified whilst still attached. Final

product is released at the end of the synthesis.

Examples of solid phase supports:

Partially cross-linked polystyrene beads hydrophobic in nature causes

problems in peptide synthesis due to peptide folding

Sheppard’s polyamide resin - more polar

Tentagel resin - similar environment to ether or THF

Beads, pins and functionalized glass surfaces

Method • Beads must be able to swell in the solvent used, and remain stable

• Most reactions occur in the bead interior

L

Anchor or linker

A molecular moiety which is covalently attached to the solid support, andwhich contains a reactive functional group

• Allows attachment of the first reactant

• The link must be stable to the reaction conditions in the synthesis but easilycleaved to release the final compound

• Different linkers are available depending on the functional group to beattached and the desired functional group on the product

• Resins are named to define the linker e.g. Merrifield, Wang, Rink

Solid phase synthesis: protecting groups

A few protecting groups used in solid phase synthesis.

For amines:

Boc ( t-butoxycarbonyl )

Fmoc (9-fluorenylmetoxy carbonyl)

Tmsec (2 [trimethylsilyl] ethoxycarbonyl)

For carboxylic acids:

Tert Bu ester(t-butyl ester)

Fm ester(9-fluronyl methyl ester)

Tmse ester(2 [trimethylsilyl] ethyl)

Parallel Synthesis To use a standard synthetic route to produce a range of analogues, with a different

analogue in each reaction vessel, tube or well.

The identity of each structure is known

Useful for producing a range of analogues for SAR or drug optimisation.

Procedure for parallel synthesis!

Houghton’s Tea Bag Procedure:

Each tea bag contains beads and is labelled

Separate reactions are carried out on each tea bag

Combine tea bags for common reactions or work up procedures

A single product is synthesised within each teabag

Different products are formed in different teabags

Economy of effort - e.g. combining tea bags for workups

Cheap and possible for any lab

Manual procedure and is not suitable for producing large quantities of different products

Automated parallel synthesis:

Automated synthesizers are available with 42, 96 or 144 reaction vessels or wells

Use beads or pins for solid phase support

Reactions and work ups are carried out automatically

Same synthetic route used for each vessel, but different reagents

Different product obtained per vessel

Mixed Combinatorial Synthesis:

To use a standard synthetic route to produce a large variety of

different analogues where each reaction vessel or tube contains a

mixture of products

The identities of the structures in each vessel are not known with

certainty

Useful for finding a lead compound

Capable of synthesizing large numbers of compounds quickly

Each mixture is tested for activity as the mixture Inactive mixtures

are stored in combinatorial libraries

Active mixtures are studied further to identify active component

The Mix and Split Method:

Example - Synthesis of all possible dipeptides using 5 amino acids

Standard methods would involve 25 separate syntheses.

Combinatorial procedure involves five separate syntheses using a mix

and split strategy

Quantitative structure activity relationship(QSAR)

QSAR is a mathematical relationship in the form of an equation

between the biological activity and measurable physiochemical

parameters.

QSAR attempts to identify and quantify the physicochemical

properties of a drug and to see whether any of these property has an

effect on the drugs biological activity

The parameters used in QSAR is a measure of the potential

contribution of its group to a particular property of the parent drug.

Activity is expressed as log(1/C). C is the minimum concentration

required to cause a defined biological response.

Physicochemical property as log p.

Various parameters used in QSAR studies are

Lipophilic parameters: partition coefficient, π- substitution constant.

Electronic parameters: Hammet constant.

Steric parameters: Taft’s constant, molar refractivity, Verloop steric

parameter.

LIPOPHILIC PARAMETERS

Lipophilicity is partitioning of the compound between an aqueous and

non-aqueous phase.

Partition coefficient: P=[drug] in octanol/[drug] in water

Linear relationship

between

Log p and Log 1/C

Non –linear

relationship

between Log P and

Log 1/C

π-substituent constant or hydrophobic substituent constants:

The π-substituent constant defined by Hansch and co-workers.

Measure of how hydrophobic a substituent is, relative to H.

Positive values imply substituents are more hydrophobic than H

Negative values imply substituents are less hydrophobic than H

A QSAR equation may include both P and p.

P measures the importance of a molecule’s overall hydrophobicity (relevant to

absorption, binding etc.)

p identifies specific regions of the molecule which might interact with hydrophobic

regions in the binding site

ELECTRONIC PARAMETERSHammett Substituent Constant (σ):

Eg. X= electron withdrawing group (e.g. NO2)

X= electron donating group (e.g. CH3)

σ value depends on inductive and resonance effects

σ value depends on whether the substituent is meta or para

ortho values are invalid due to steric factors

STERIC SUBSTITUTION CONSTANT

It is a measure of the bulkiness of the group it represents and it effects

on the closeness of contact between the drug and receptor site. It is

much harder to quantitate.

Taft’s steric factor (Es') : Measured by comparing the rates of

hydrolysis of substituted aliphatic esters against a standard ester under

acidic conditions

Es = log kx - log ko

kx represents the rate of hydrolysis of a substituted ester

ko represents the rate of hydrolysis of the parent ester

Molar refractivity (MR): Measure of the volume occupied by an atom or group--

equation includes the MW, density(d), and the index of refraction

(n)– MR=(n²-1)MW/(n²+2)d

Verloop steric parameter: computer program uses bond angles, van der Waals radii,

bond lengths.

Hansch Equation

A QSAR equation relating various physicochemical properties to the biological

activity of a series of compounds

Usually includes log P, electronic and steric factors

Start with simple equations and elaborate as more structures are synthesised

Typical equation for a wide range of log P is parabolic

Conclusions:

• Activity increases if p is +ve (i.e. hydrophobic substituents)

• Activity increases if s is negative (i.e. e-donating substituents)